X-ray contrast agent



3,047,466 X-RAY CONTRAST AGENT Hans Priewe, Berlin-Steglitz, AlexanderPoljak, Berlin- Frohnan, and Karl Junkmann, Berlin, Germany, assignorsto Firma Schering A.G., Berlin, Germany No Drawing. Filed Dec. 9, 1958,Ser. No. 779,065 Claims priority, application Germany Dec. 18, 1957 12Claims. (Cl. 167-95) The present invention relates to X-ray contrastagents, and more particularly to X-ray contrast agents suit-able forperoral administration to serve as a contrast agent for the taking ofX-ray pictures of the gall bladder and in general for cholecystography.

It is a primary object of the present invention to provide new X-raycontrast agents for peroral administration which are suitable forcholecystography.

It is another object of the present invention to provide for theproduction of the new compounds of the present invention.

*Other objects and advantages of the present invention will be apparentfrom a further reading of the -specification and of the appended claims.

With the above objects in view, the present invention mainly comprises acompound selected from the group consisting of compounds of thefollowinggeneral formula:

1 R HzN I wherein R is a hydrocarbon radical of 1-6 carbon atoms, andnon-toxic salts thereof.

It has been discovered that while a-alkyl-fl-(B-amino-2,4,6-triiodophenyl) -propionic acids are suitable as X-ray contrastagents for the taking of X-ray pictures of the gall bladder, the diaminocompounds of the present invention have many advantages over the abovementioned monoamino compounds.

Among the advantages of the compounds of the present invention are:considerably lower toxicity, a markedly excellent resorbability uponperoral administration, and a preferred deposition in the gall with asimultaneous increased degree of contrast development. Furthermore, thenew compounds of the present invention have the advantage of being ableto leave the body, if necessary, through the urinary tract, which in thecase of occlusions of the bile duct represents a considerable advantageas compared to the above mentioned monoamino compounds which do not havethis property.

The compounds of the present invention are primarily useful asradiopaque substances to be given orally for cholecystography, thesecompounds being given in the form of the free acids or in the form oftheir non-toxic salts. The compounds may also, however, be given for thepurpose of taking X-ray pictures of other organs than the gall bladder,such as body cavities in general.

As indicated above, the substituent R is a hydrocarbon radical ofpreferably 1-6 carbon atoms. Preferably, the substituent R is an alkylor cycloalkyl radical of l-6 carbon atoms.

The compounds may be used in the form of the tree acids or in the formof non-toxic salts thereof with inorganic or organic bases. Among thesuitable salts which may be mentioned are: the methylglucamine,ammonium, sodium, lithium, potassium, calcium, glucamine,ethylglucamine, ethanol-amine, diethanolamine and triethanolamine salts.

The compounds may be mixed with suitable pharmaceutical excipients andmade up into a form suitable for 3,647,466 Patented July 31, 1962 ice 2oral administration, for example in the form of capsules, dragees, andthe like.

The compounds of the present invention are preferably produced byiodinating a compound having the following general formula:

may be produced according to the methods generally used in organicsynthesis for the production of similar compounds, for example from3,5-dinitrobenzoyl-acetic ester by introducing into the zit-position inknown manner the desired aliphatic or cycloaliphatic radical. This iscarried out, for exam le, by reacting the sodium enolate of the3,S-dinitrobenzoyl-acetic ester in alcoholic solution with an alkyl orcycloalltyl halogenide, e.g. chloromethyl, isopropylbromide,hexyliodide, or the like. Upon hydrogenation the corresponding,8-3,5-diaminophenyl- 8- hydroxy-a-alkyl. or cycloalkyl-propionic acidester is obtained. By reaction with thionyl chloride, the ,B-positionhydroxyl is replaced by chlorine, which is subsequently replaced byhydrogen by means of hydrogenation.

The following examples are given to further illustrate the presentinvention. The scope of the invention is not, however, meant to belimited to the specific details of the examples.

Example 1 18 g. of a-ethyl-B-(3,5-diaminophenyl)-propionic acidethylester are heated for saponifioation with a mixture of 150 cc. of 3 Nsodium hydroxide and 250 cc. of methanol for 3 hours to boiling underreflux conditions. The reaction mixture is then acidified with dilutehydrochloric acid and the methanol is driven ofi under vacuum.

The distillation residue is diluted with ice water to 1200 cc. and 90cc. of 2 N potassium iodide-dichloride solution is added dropwise understirring. The precipita ted sand colored precipitate is subjected tosuction filtration, washed with water and dissolved in ether.

The solution which is dried over sodium sulfate is reacted withalcoholic sodium hydroxide which results in precipitation of the sodiumsalt of u-ethyl-B-(3,S-diarnino 2,4,6-triiodophenyl)spropionic acid. Thesalt is filtered by suction, dissolved in water, and the free acid isprecipitated from the aqueous solution by means of dilute hydrochloricacid. The yield of the air-dried product is 24 g. The melting point isabove C., with decomposition.

By treatment with benzene under cold conditions and subsequentrecrystallization from a large amount of benzene, the substance isobtained in the form of practically colorless crystals having a meltingpoint of 156.5- 157 C., with decomposition. The salt may be obtained byneutralization of the acid in aqueous solution with the correspondingbase, and then freezing-drying.

Example 2 10 kg. of the methyl-[H3,S-diamino-2,4,6triiodophenyl)propionic acid produced according to Example 1 are kneadedin a kneading machine with 4 liters of starch paste containing 200 g. ofcorn starch. The wet mass is granulated in a normal manner in agranulation machine and then dried under vacuum. The finished granulateis then mixed with 1 kg. of corn starch and 50 g. of magnesium stcarateand pressed into tablets each containing 500 mg. of the activeingredient.

Example 3 The easily water soluble sodium salt of methyl-543,5-diamino-2,4,G-triiodophenyl)-propionic acid produced according toExample 1 is introduced into gelatin capsules filling the same. Eachcapsule contains 750 mg. of the active substance. For machine productionof capsules the sodium salt can be mixed with a 40% mixture of corn oil,soybean lecithin and cocoa fat to a flowing paste.

Example 4 The granulate produced according to Example 2 is with 20% ofthe weight thereof of sugar syrup formed into dragees in a drageevessel, and subsequently waxed.

Without further analysis, the foregoing will so fully reveal the gist ofthe present invention that others can by applying current knowledgereadily adapt it for various applications without omitting featuresthat, from the standpoint of prior art, fairly constitute essentialcharacteristics of the generic or specific aspects of this inventionand, therefore, such adaptations should and are intended to becomprehended within the meaning and range of equivalence of thefollowing claims.

What is claimed as new and desired to be secured by Letters Patent is:

'1. A compound selected from the group consisting of compounds ofthefollowing general formula:

HZN I wherein R is a hydrocarbon radical of 1-6 carbon atoms; andnon-toxic salts thereof.

2. A compound having the following general formula:

rnN r r-Q-om-cn-ooon 1 1i H2N I wherein R is an alkyl radical of =1-6carbon atoms.

3. A compound having the following general formula:

' HQN I- -CH2-(I3H-COOH 1 R HnN I wherein R is a cycloalkyl radical of1-6 carbon atoms. 4. A non-toxic salt of a compound having the followinggeneral formula:

wherein R is an alkyl radical of 1-6 carbon atoms.

5. A nontoxic salt of a compound having the following general formula:

wherein R is a cycloalkyl radical of 1-6 carbon atoms.

6. The sodium salt of a compound having the following general formula:

wherein R is an alkyl radical of l-6 carbon atoms.

7. The sodium salt of a compound having the following general formula:

Hal 1 wherein R is a cycloalkyl radical of 1-6 carbon atoms.

8. The methylglucamine salt of a compound having the'foll-owing generalformula:

wherein R is an alkyl radical of 1-6 carbon atoms.

9. The methylglucamine salt of a compound having the following generalformula:

R H N I R iN wherein R is a hydrocarbon radical of 1-6 carbon atoms, andnon-toxic salts thereof; and pharmaceutical excipients adapted forpero-ral administration.

References Cited in the file of this patent UNITED STATES PATENTS2,705,726 Archer Apr. 5, 1955 2,820,814 Grinsberg Jan. 21, 19582,921,884 Nachod Jan. 19, 1960 FOREIGN PATENTS 782,313 Great BritainSept. 4, 1957

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFOLLOWING GENERAL FORMULA: